PI3Kγ is a molecular switch that controls immune suppression

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer(1-5). In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors(1-7). Here we show that macrophage PI 3-kinase gamma controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3K gamma signalling through Akt and mTOR inhibits NF kappa B activation while stimulating C/EBP beta activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3K gamma stimulates and prolongs NF kappa B activation and inhibits C/EBP beta activation, thus promoting an immunostimulatory transcriptional program that restores CD8(+). T cell activation and cytotoxicity. PI3K gamma synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3K gamma-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.